1. Field of the Invention
The present invention relates to a method for producing an alkyl 3-phthalidylideneacetate used as a synthesis intermediate for synthesizing 4-oxo-3-phthalazin-1-yl acetic acid useful as aldose reductase inhibitors for treatments of various chronic complications caused by diabetes, such as cataract, retinopathy, and neuropathy due to diabetes.
2. Discussion of the Related Art
Conventionally, the methods for producing an alkyl 3-phthalidylideneacetate are as follows:
(1) A method comprising the steps of treating phthalic anhydride with potassium acetate in acetic anhydride, treating with thionyl chloride, and then esterifying the product with an alcohol (see U.S. Pat. No. 2,483, 371); PA1 (2) A method of treating phthalic anhydride with ethoxycarbonylmethylenetriphenylphosphorane in chloroform (see Aust. J. Chem., 1975, 28, 2499-2510); PA1 (3) A method comprising the steps of treating phthalic anhydride with a zinc-copper couple and ethyl bromoacetate (Reformatsky reaction), and dehydrating the reaction product with a concentrated sulfuric acid (J. Org. Chem., 1991, 56, 2587-2589, and Japanese Pat. Laid-Open No. 64-3173); and PA1 (4) A method of treating phthalic anhydride with diethyl malonate in toluene (see J.C.S Perkin I, 1977, 84-90).
However, the method (1) comprises many steps, and the yield of the product is low. Also, it uses thionyl chloride, thereby making it industrially disadvantageous. In the method (2), triphenylphosphorane is used, and a mixture of cis-trans isomers is produced. In the method (3), the yield of the Reformatsky reaction is undesirably low, and metal waste water problems are incurred by the use of Zn and Cu. Further, the reaction is carried out in a two-step process. The method (4) is a two-step process, and the yield is extremely low (13%), making it industrially disadvantageous. The reasons for a low yield in the method (4) are not clear from the reference, but they may be presumably as follows:
Although the yield of the intermediate product of the two-step reaction in the method (4) is not disclosed in the reference, an extremely low yield (9%) of ethyl cyano(phthalidylidene)acetate, obtained by a similar reaction to the first step of the method (4), suggests a low yield of the intermediate in the method (4). In addition, a selective hydrolysis of only one of esters of diethyl malonate to give only a Z-isomer further lowers the product yield. Moreover, an E-isomer may be undesirably produced as a side product in the second step of the method (4).
Accordingly, a development of a more industrially advantageous method for producing an alkyl 3-phthalidylideneacetate is in demand.